Pertussis remains a major epidemiological burden, accounting for roughly 300,000 deaths worldwide each year, most of them children. The early success of infant immunization programs in the 1950s and 1960s led to a substantial reduction in incidence and a sense of optimism that elimination of pertussis might be a achievable. Over the past two decades, however, documented outbreaks in a number of well vaccinated populations has pointed out major gaps in our understanding of pertussis epidemiology, immunology, evolution, and control. The availability and use of various vaccines with poorly understood efficacy and immunity profiles contributes to the uncertainty. We propose to improve our understanding of these important determinants of pertussis transmission by splitting the problem into manageable units. By conducting a comprehensive, comparative testing of multiple alternative hypotheses on long-term, spatially replicated, and age-specific data from different countries in the pre-vaccine era, we will aim to pin down the duration of infection-derived immunity, the epidemiological impact of repeat infections, the role played by sub-clinical immune boosting, and the respective contributions of population demography, age-specific contacts, and seasonality. The next phase of research will aim to address the vaccine-specific aspects of the problem by focusing on countries with known vaccine usage (whole cell vs. a cellular) and immunization schedules. The ultimate test of whether our understanding of pertussis has significantly advanced will be to explain an enigmatic body of data, namely the changing patterns of pertussis incidence in the US over the past thirty years. This work will rely heavily on the use of mathematical models of pertussis transmission and statistical methods for extracting information from data. A major ingredient in this project, therefore, is the development, use, and dissemination of novel methodological tools that will be implemented in open-source public software. Finally, we will bring together the intellectual fruits of this effortin order to develop optimal, cost-effective immunization policy. PUBLIC HEALTH RELEVANCE: The control of infectious diseases by means of immunization remains a critical public health priority. In some nations, including the US, recent decades have coincided with a notable increase in pertussis notifications, despite high vaccine uptake estimates pinpointing significant knowledge gaps in pertussis biology. Therefore, understanding the complex interaction of factors that affect pertussis epidemiology, immunology, evolution, and control is an urgent priority. This is what we propose to do using an extensive database of pertussis reports from a number of countries, including information on age, geography and serotype. We will test alternative competing hypotheses using these data and cutting edge statistical methods. Finally, we will distill the intellectual fruits of this effort into optimal, ost-effective immunization policy.